Development of the mammalian central nervous system (CNS) requires the production of many types of neurons and glia at the correct numbers and appropriate locations. The controlled proliferation, differentiation and migration of multipotent neural progenitor cells give rise to these diverse cell types and are critical for proper CNS development. Abnormalities in these processes have been implicated in microcephaly and in several forms of mental disorders including mental retardation, depression, and schizophrenia. Furthermore, stem cell-based cell replacement therapy offers enormous potential for the treatment of a variety of developmental, psychiatric, neurodegenerative and aging related diseases for which there are currently no cures. The elucidation of molecular mechanisms that regulate neural progenitor cell differentiation into neurons is important for an understanding of human developmental and neurodegenerative diseases. The multipotent neural progenitor cells can differentiate into neurons or glia depending on developmental cues and environmental signals. Neuron differentiation proceeds by a 2-step process: the initial commitment of the progenitors to a neuronal fate followed by terminal differentiation of the committed precursors into mature neurons. The specification of cortical progenitors to a neuronal fate requires a coordinated expression of the basic-helix-loop-helix (bHLH) family of transcription factors neurogeninl (Ngn1) and neurogenin2 (Ngn2). The transient expression of proneural Ngn1 and Ngn2 induces the expression of the NeuroD family of bHLH differentiation genes (NeuroD, NeuroD2 and Nex), which mediate terminal differentiation of neurons. Despite the known role for Ngn/NeuroD in the development of the CNS, little is known regarding the molecular mechanisms underlying regulation of the commitment of the progenitors to a neuronal fate by the proneural factors Ngn 1 and Ngn2. For example, the signaling pathways and mechanisms that positively regulate the activity of Ngns are completely unknown. In this proposal, we will investigate a potential role for the ERK5 MAP kinase signaling pathway in cell fate specification of cortical progenitor cells. [unreadable] [unreadable]